Acute hepatitis with unknown etiology amidst the COVID-19 and monkeypox time: an emerging global concern among the children
Authors: Dattatreya Mukherjee, Prashant Upadhyay, Nobendu Mukerjee, Sri Jamya, Anuj Paul, Arpita Dandapat, Sourav Chakraborty, Tapati Pradhan, Debayan Podder, Puspendu Biswas
Journal: International Journal of Surgery (2023)

Highlights Many countries are reporting cases with acute severe hepatitis without any identifiable cause among young children. Hepatitis may be due to sudden increase in severe hepatitis cases after coronavirus disease 2019 (COVID-19) pandemic or due to increase in awareness and laboratory testing for hepatitis. As a preventive action, COVID-19 vaccination should be encouraged globally in healthy children to break the possible chain of transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in communities. Dear Editor, Many countries are reporting cases with acute severe hepatitis without any identifiable cause among young children. This sudden surge of cases has been observed after the WHO published disease outbreak news on 23 April 2022. It may be due to sudden increase in severe hepatitis cases after COVID-19 pandemic or due to increase in awareness and laboratory testing for hepatitis1. According to the WHO report, approximately all cases were in the range of 1 month to 16 years of age. Among which nearly 10% required liver transplantation and one mortality was reported1. In European countries, 75.4% of the cases are aged below 5 years and are mostly clustered between 1 month and 16 years of age1,2. These children are presenting with symptoms of abdominal pain, diarrhea, vomiting, acute hepatitis with elevated liver enzymes (aspartate transaminase, alanine transaminase greater than 500 IU), and mild jaundice. Fever was absent in the majority of cases and serology for the commonly known hepatotropic viruses causing hepatitis-like hepatitis A, B, C, D, E viruses was also negative, thus the exact pathophysiology and mode of transmission are still unclear3,4. Currently, around 74 cases were found positive for adenovirus which on further molecular testing was identified as type F41 among 18 of the total cases. SARS-CoV-2 was identified in 20 and 19 cases were detected with a SARS-CoV-2 and adenovirus co-infection1, the etiology is accepted to be adenovirus type F41 and many countries are also reporting enhanced community circulation of adenoviruses. Adenoviruses often cause minor respiratory symptoms; however, they have previously been linked to hepatitis in immunocompromised children. In this context, a recent WHO report showed that out of 63 cases with data available on COVID-19 vaccination status, 53 (84.1%) were not vaccinated1. This might be due to an undetected latent SARS-CoV-2 infection that is now manifesting as CAH (COVID-19-acquired hepatitis)5. It is further supported by the fact that post COVID liver injuries are also being reported in adults as well6. In a study, two pediatric patients presenting with post COVID-19 hepatic symptoms underwent liver biopsies and the explant of two infants requiring liver transplant shows massive necrosis along with bile duct proliferation and lymphocytic infiltrate was evident6. Some researchers believe that previous exposure to SARS-CoV-2 genetic variants like B.1.1.529 may have enhanced the risk of severe hepatitis. They reported at least one acute severe hepatitis case among 12 of 39 countries included in the study and number of confirmed SARS-CoV-2 genetic variant (mostly Omicron B.1.1.529 variant) cases in these 12 countries found to be between 4.4 and 11.9 million5. Of 181 cases, 60.8% were positive for adenovirus, 12.2% cases positive for SARS-CoV-2 ,and it was observed that 133 cases were positive for both the viruses1. Population-based serological testing in the affected countries will probably show a greater number of children suffering from acute severe hepatitis having past or recent SARS-CoV-2 infection7. In a study done by Yarovinsky et al.8, it was reported that adenovirus infection in mice sensitizes the mice for severe Staphylococcus enterotoxin B-mediated toxic shock causing interferon-gamma–mediated apoptosis of hepatocytes subsequently leading to liver failure. This suggests that adenovirus infection might serving as an initiating sensitizing agent while the main culprit may be superantigen-mediated immune activation by the SARS-CoV-2 spike protein superantigen leading to acute hepatitis (liver damage)8. This hypothesis is further supported by the co-infection of adenovirus and SARS-CoV-2 present among 19 cases1 and also there is good response seen with steroid therapy indicating it to be of autoimmune-mediated damage to liver6. WHO and UKHSA (UK Health Security Agency) recommends the investigation of blood, serum, urine, stool, and respiratory samples along with viral sample sequencing. It is also recommended to thoroughly investigate other possible risk factors like infectious and noninfectious diseases, metabolic and hereditary conditions, environmental exposures (toxins), and autoimmune conditions to rectify and enhance the control and prevention actions1,3. Other factors like diet and immunocompetency should also be kept in mind. Recently, hepatitis A outbreak after intake of organic strawberry is an notable example towards this.9 WHO has made a clinical case reporting form for the acute hepatitis of unknown etiology for the systematic data collection and also setting a network of regional and global referral laboratories to overcome the limitations of testing in local laboratories1 Currently, the outbreak is confined in a limited area in the world, but as there is a connection with COVID-19 co-infection, so this situation is creating a truly global concern. Further research and investigations for co-viral infections and evaluation of other environmental factors needed to be done keeping in mind that SARS-CoV-2 autoimmune-mediated complications can be one of the possible factors responsible for the global surge of severe acute hepatitis cases. A total of 650 cases have been reported from 33 countries.1 As a preventive action, COVID-19 vaccination should be encouraged globally in healthy children to break the possible chain of transmission of SARS-CoV-2 in communities, WHO recommends some preventable practices such as practicing proper hand hygiene, wearing masks, preventing contamination of food and water, not going to crowded places1. Other vaccines like hepatitis A and B should be administered among the community. Government of both affected and unaffected countries should prepare a standard operating procedure on vaccinations to combat this situation (Fig. 1). The pediatric hepatologist should counsel parents for proper vaccination schedule for their children to reduce such fatal risk. Early identification of cases is critical in the optimum case management. The exact cause should be known as early as possible. It is also important to find out the exact pathophysiology of hepatitis of unknown origin. Globally monkeypox cases are now increasing.10 Recently, in the USA, hepatitis A outbreak has happened due to organic strawberries.11 In India, a new disease is making concern, that is, tomato fever, but many experts are also thinking that this is only an outbreak of hand foot mouth disease.12 COVID-19 cases are also increasing globally. So, currently, hepatitis of unknown origin is making a great concern towards global health. New clinical trials should be started on this. New treatment guidelines should be prepared. Bioinformatics and computational biology can be used to design new drugs and efficacy can be predicted through artificial intelligence. A database for cases and mortality should be prepared. All hospitals should register the cases in a common database. Every country government should create an expert team who will eventually prepare a standard operating procedure. Country-based hepatitis strategic team can be prepared. More clinical data and researches are needed to combat this situation in a very early phase. With a collaborative work and proper scientific researches, we can combat this situation is an early phase.Figure 1: The procedure to control the outbreak of hepatitis of unknown origin.Ethical approval Not applicable. Sources of funding None. Authors’ contribution D.M., P.U., D.P., and P.B.: conceptualize. P.U., S.J., A.P., A.D., S.C., and T.P.: writing. N.M.: image preparation. D.M., D.P., P.B., A.P., and N.M.: critical review. P.U., D.M., A.D., S.C., and T.P.: editing. Conflicts of interest disclosure The authors declare that they have no financial conflict of interest with regard to the content of this report. Research registration unique identifying number (UIN) None. Guarantor All authors.